Autistic endophenotypes and their associations to oxytocin and cholesterol

描述（由申请人提供）：这是一份为期两年的资助申请，响应PA-06-391：自闭症和自闭症谱系障碍研究R03。临床、动物和遗传证据都指出了催产素在自闭症中的作用，并表明催产素相关的异常可能存在于自闭症先证者的亲属中。一些具有挑衅性的线索对胆固醇也提出了类似的可能性。在拟议的试点研究中，我们计划评估30个家庭（尽管其中15个家庭将通过其他方式资助）的血液样本中的催产素和胆固醇水平，每个家庭都有一个孩子被诊断为自闭症或自闭症谱系障碍，20个家庭没有自闭症家庭成员。从这个小项目中获得的初步数据将帮助我们设计一个更大的项目，目的是通过改善对表型表达的描述，最终找到自闭症的易感基因。参与的自闭症先证者家庭也将有未受影响的孩子。这将使我们不仅可以比较自闭症父母和对照组父母，还可以比较自闭症兄弟姐妹和对照组兄弟姐妹。我们将对所有参与者进行自闭症筛查，随后对可能受影响的儿童进行诊断评估。此外，我们将评估催产素和胆固醇与自闭症的三个核心症状域（社交缺陷、沟通和行为异常）以及执行功能相关的行为和神经心理特征之间的潜在关系。虽然这些评估中的许多已经成功地用于自闭症家庭研究；其他的还没有用于自闭症家庭研究，因此是探索性的。除了与催产素和胆固醇的关系之外，这些测量将作为评估更具体的行为和神经心理特征的工具，即所谓的内表型。最后，使用一种新的统计方法，多元距离矩阵回归方法，以前没有在自闭症及其亲属的研究中使用，我们将尝试确定家庭中的亚群，即可以通过独特的内表型特征来描述的家庭。阐明自闭症家族的内表型和亚群都是通过分子遗传学研究寻找相关基因的有用措施。因此，我们的研究将为确定自闭症的病因提供必要的信息。公共卫生相关性：由于自闭症和自闭症谱系障碍在遗传上是复杂的，与这种疾病有关的基因在很大程度上仍然是未知的。我们建议进行一项研究，旨在分离出不同的行为和认知特征，以及它们与催产素和胆固醇的关系，这两种有机生物化学物质可以在血液中测量，被假设为自闭症先证者及其家庭中显示异常。这将带来非常重要的新信息，可以告知和加强自闭症和ASD的遗传研究，从而有助于揭示这组严重发育障碍的原因。

DESCRIPTION (provided by applicant): This is a 2-year grant application in response to PA-06-391: Research on Autism and Autism Spectrum Disorders R03. Clinical, animal, and genetic evidence points to a role for the hormone oxytocin in autism and suggests that oxytocin related abnormalities may be present in relatives of autism probands. Provocative clues raise a similar possibility for cholesterol. In the proposed pilot study, we plan to assess oxytocin and cholesterol levels in blood from a sample of 30 families (although 15 of these families will be financed through other means) each with a child diagnosed with autism or autism spectrum disorder and 20 families without autistic family members. The preliminary data obtained from this small project will help us design a larger one aimed ultimately at finding susceptibility genes for autism through the improved delineation of phenotypic expressions. Participating autism proband families will also have unaffected children. This will enable us to compare not only autism parents with control parents but also autism siblings with control siblings. We will screen all participants for autism and will subsequently use diagnostic assessments for potentially affected children. Furthermore, we will assess potential relationships between both oxytocin and cholesterol with behavioral and neuropsychological traits associated with the three core symptom domains of autism (social deficits, communication, and behavioral abnormalities), as well as executive functions. While many of these assessments have been used successfully in autism family studies; others have not been used in autism family studies before and are thus exploratory. Beyond their relationships with oxytocin and cholesterol, these measures will serve as a tool to evaluate more specific behavioral and neuropsychological traits, so called endophenotypes. Finally, using a new statistical method, multivariate distance matrix regression methodology, not previously employed in studies of autism or their relatives, we will try to identify subgroups within families, that is, families that can be described through a distinct endophenotypic profile. Clarifying endophenotypes and subgroups within autism families are both useful measures in the search for associated genes through molecular genetic studies. Accordingly, our study will contribute to the information necessary to define the causal factors of autism. PUBLIC HEALTH RELEVANCE: Because autism and autism spectrum disorder are genetically complex, the genes involved in this disorder are still largely unknown. We propose to conduct a study designed to isolate distinct behavioral and cognitive traits and their connections to oxytocin and cholesterol, two organic bio-chemicals that can be measured in the blood that are hypothesized to show abnormalities in autistic proband and their families. This will lead to very important new information that can inform and strengthen genetic studies of autism and ASD and thus help reveal the causes of this severe group of developmental disorders.